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Characteristic features on physical examination

Necrobiosis lipoidica (NL) typically presents on the anterior tibial areas and ankles as firm smooth annular plaques. The peripheral rims of the plaques are red, violet, or brown, and the atrophic central portions are often yellow or pink (Figure 1, Figure 2). Varicosities and telangiectasias may be visible through the intact, atrophic skin (Figure 3). Focal scale may be present, especially in the atrophic centers. Although usually asymptomatic, NL may be associated with pain or pruritus. Ulceration occurs in one-third of cases. Necrobiosis lipoidica has occasionally been reported to involve other sites, such as the face, scalp, upper extremities, or trunk.

Figure 1.

Necrobiosis lipoidica.

Figure 2.

Necrobiosis lipoidica with central crust.

Figure 3.

Histopathologic features are distinctive, and in the appropriate clinical setting, are diagnostic. Punch biopsy is most suitable. On low-power microscopy, the specimen has a square silhouette. Throughout the full thickness of the dermis, zones of palisading granulomatous inflammation alternate with zones of degenerated collagen (Figure 4, Figure 5).

Figure 5.

The differential diagnosis of NL includes principally granuloma annulare and necrobiotic xanthogranuloma, both of which share clinical and histopathologic similarities with NL. All three entities demonstrate palisading granulomas histopathologically. Table I summarizes the key differences.

The differential diagnosis less commonly includes other entities. Morphea on the anterior tibial areas may clinically mimic NL, but histologically lacks the characteristic granulomatous dermal infiltrates of NL. Early lesions of NL clinically may resemble diabetic dermopathy or stasis dermatitis. All share a similar anatomic distribution, but differ in their subsequent clinical evolution an in their histopathology. Sarcoidosis may localize to the anterior tibial areas and may show annular features, but also differs histopathologically. Sarcoidal granulomas are tight ovoid aggregates of epithelioid histiocytes without necrobiosis of the dermal collagen; whereas, the granulomatous infiltrates of NL are palisaded and associated with prominent necrobiosis.

NL and erythema nodosum may occasionally have a similar clinical appearance, but also differ histopathologically. The granulomatous infiltrates of NL are localized predominantly to the dermis; the granulomatous inflammation of erythema nodosum is centered upon the panniculus. NL, particularly if ulcerated, may clinically resemble a deep fungal or mycobacterial infection. In such cases, tissue cultures and special histologic stains for microorganisms assist in the diagnosis.

Table I. Differential diagnosis for necrobiosis lipoidica

Table I.

Differential diagnosis for necrobiosis lipoidica

Necrobiosis Lipoidica

Granuloma Annulare

Necrobiotic Xanthogranuloma

Clinical Features

Anatomic distribution

Legs, occasionally face, scalp, arms

Dorsal hands, dorsal feet, legs, trunk, or widespread

Periorbital, face, occasionally elsewhere

Clinical associations

Diabetes mellitus

No well-established associations

Paraproteinemia

Histopathologic Features

Dermal infiltrate

Diffuse, full thickness

Multifocal, scattered

Diffuse, full thickness, and massive

Dermal mucin

Negative

Focally abundant

Negative

Lymphoid aggregates

Occasional

Absent

Common

Cholesterol clefts

Occasional

Absent

Common

Multinucleate giant cells

Numerous

Moderate

Numerous, sometimes with bizarre morphology

Plasma cells

Common

Rare

Common

Who is at Risk for Developing this Disease?

Necrobiosis lipoidica (NL) is frequently associated with type I or type II diabetes mellitus. Eleven to 65% of NL patients are diabetic. The onset of NL may follow, accompany, or precede the diagnosis of diabetes mellitus. Although a substantial percentage of NL patients are diabetic, only a small percentage (0.3 to 3%) of all diabetic patients have NL.

The female to male ratio is 3:1. Mean age of onset is in the third decade. NL is rare in childhood. Children with NL typically have type I diabetes mellitus.

What is the Cause of the Disease?

Etiology

The etiology is unknown.

Pathophysiology

Theories of pathogenesis are diverse and include a T-cell mediated hypersensitivity reaction, an immune-mediated vasculopathy, or a primary degenerative disorder of dermal collagen.

Systemic Implications and Complications

In patients with a known history of diabetes mellitus, necrobiosis lipoidica may be associated with increased risk of retinopathy and proteinuria. If the patient is not already known to be diabetic, a new diagnosis of NL should prompt diagnostic screening and or higher.

Chronic ulcers may occur as a complication of NL, particularly on the legs. Rarely, squamous cell carcinoma may develop within ulcerated plaques of NL.

Treatment Options

Treatment options are summarized in Table II.

Table II.

Treatment options for necrobiosis lipoidica

Medical Treatment

Surgical Procedures

Physical Modalities

Topical corticosteroids

Topical PUVA

Tacrolimus ointment

Protease-modulating dressings

Tretinoin cream

Split thickness autologous skin graft

Photodynamic therapy

Topical granulocyte-macrophage colony-stimulating factor

Tissue-engineered dermal skin graft

Hyperbaric oxygen

Topical bovine collagen particles

UVA-1 phototherapy

Intralesional triamcinolone

Intralesional etanercept

Pentoxifylline

Nicatinamide

Hydroxychloroquine

Chloroquine

Pioglitazone

Aspirin /Dipyridamole

Etanercept

Clofazimine

Mycophenolate mofetil

Systemic corticosteroids

Thalidomide

Cyclosporine A

Infliximab

Optimal Therapeutic Approach for this Disease

Treatment of NL is challenging. Therapeutic recommendations in the literature are based mostly upon case reports and uncontrolled small series of patients.

Topical and intralesional corticosteroids may be beneficial, but the risk of further atrophy and ulceration must be considered. Clobetasol propionate 0.05% ointment or cream or fluocinonide 0.05% ointment or cream may be applied twice daily, with or without occlusion, to the peripheral inflammatory rim of the lesions. As the inflammation diminishes over 2 to 3 weeks, the higher strength corticosteroid may be replaced by one of a moderate strength, such as triamcinolone acetonide 0.1% ointment or cream, applied twice daily to the peripheral inflammatory rim.

The central portions of the plaques are often atrophic and less suitable for topical corticosteroid therapy. White petrolatum may be applied to the central atrophic areas to protect them from exposure to the adjacent corticosteroids, especially if the corticosteroids are applied under occlusion.

Intralesional injection of corticosteroids is an alternative to topical preparations, particularly if the patient has a single lesion or very few lesions. Intralesional injections should similarly be focused upon the peripheral inflammatory rim, rather than on the atrophic central area. Triamcinolone acetonide 3 mg/mL may be injected intradermally into the inflammatory peripheral rim, approaching from the perimeter of the plaques. Lidocaine cream may be useful as a topical anesthetic, applied prior to the injections.

Reassessment of the patient in 6 weeks may be considered to monitor the response to treatment. Additional intralesional injections may be repeated as necessary, while monitoring the patient for signs of atrophy or ulceration.

Tacrolimus 0.1 % ointment has been noted for its effectiveness in several reported cases of NL. Unlike corticosteroids, tacrolimus does not induce cutaneous atrophy. Accordingly, tacrolimus ointment may be specifically useful for the central areas of the plaques, which are often atrophic or ulcerated. Tacrolimus has been reported to produce healing of the central ulcer, even though the peripheral inflammatory rim may not respond as well to treatment. For patients with ulcerated inflamed plaques of NL, tacrolimus ointment may be applied to the central ulcer, while topical corticosteroids are reserved for the peripheral rims.

In prescribing tacrolimus, it should be noted that the medication currently carries a black box warning from the FDA due to concerns that its long term safety has not been established. As a result, it is reasonable to discuss the concerns with the patient and explain that the use of tacrolimus for NL is off-label. Potential benefits and theoretical risks of tacrolimus can be considered in discussion with the patient, before a therapeutic recommendation is made.

Tretinoin cream 0.025% or 0.05 % may be another helpful treatment, particularly for atrophic, nonulcerated lesions. At least two case reports describe the usefulness of tretinoin cream in partially reversing the atrophy associated with NL.

Multiple reports describe topical psoralen plus ultraviolet A (PUVA) as a very effective treatment, using protocols similar to those used for localized psoriasis of the hands and feet. Burning, blistering, and prolonged localized photosensitivity are potential adverse reactions. A separate study of UVA1 showed less consistent effectiveness.

Among systemic therapies, pentoxifylline (400mg by mouth three times daily) is a leading consideration. Other relatively low-risk therapeutic choices include nicotinamide (200 to 500mg by mouth three times daily) or antimalarials (hydroxychloroquine 400mg daily or chloroquine 200-300mg daily). Antiplatelet agents have also been proposed as a treatment option, but a randomized double-blind placebo controlled trial of combined aspirin and dipyridamole did not demonstrate significant benefit over placebo.

A variety of other systemic medical therapies, as listed above, have been reported to be successful in isolated cases or small series of patients. These options, including systemic corticosteroids, thalidomide, cyclosporine A, or infliximab, may be considered for severely symptomatic patients, but the possible benefits would need to be weighed carefully against the potential risks. Systemic corticosteroid therapy may induce hyperglycemia in diabetic patients and needs to be paired with close glycemic control. Nevertheless, a case series of 6 patients revealed marked improvement and lasting benefit after a course of oral methylprednisolone (1mg/kg/day by mouth for 1 week, followed by 40mg/day for 4 weeks, then tapered and discontinued after 2 more weeks).

Etanercept may be helpful in the treatment of NL. In a recent case report, etanercept resulted in significant improvement with a standard regimen of 50mg injected subcutaneously twice weekly for 3 months and then weekly. Adalimumab 40mg injected weekly did not appear to be as effective in the same patient. Another report describes a novel approach of intradermal injection of etanercept directly into a plaque of NL. Etanercept 25mg was injected intradermally at 1-cm intervals along the perimeter of a single plaque, after topical anesthesia with 4% lidocaine cream. Weekly injections resolved the plaque after 8 months.

Ulcerated NL is particularly difficult to treat. A variety of medical, surgical, and physical modalities may be beneficial and are sometimes useful in combination. Management recommendations for ulcerated NL are included in Unusual clinical scenarios to consider in patient management.

Patient Management

For many patients, NL is primarily a cosmetic problem without associated symptoms. For those patients, maintenance therapy with low-risk topical medication is a reasonable long-term approach. Goals of therapy should include the prevention of ulceration, by careful protection of the legs from trauma.

Patients with more severe complications, such as painful chronic ulcers, require close follow-up and may require maintenance therapy with systemic and topical medications, as listed above. For those patients, goals of treatment are the healing of ulcerations and the relief of associated pain.

The effect of glycemic control upon the clinical course of NL is unclear and is debated in the literature. Smoking has been occasionally cited as a contributing factor in the development of NL, but the benefit of smoking cessation upon the clinical course of NL has not been systematically analyzed. Nevertheless, given the known overall health benefits of glycemic control and smoking cessation, these recommendations will at least provide benefit to the patient's overall health and may potentially improve the lesions of NL as well.

Unusual Clinical Scenarios to Consider in Patient Management

Although NL is typically localized to the anterior tibial region, involvement of other anatomic sites has occasionally been reported. Uncommon sites include the scalp, face, upper extremities, and trunk. When the diagnosis of NL is considered for lesions on atypical sites, biopsies are indicated to exclude other entities in the differential diagnosis. So-called atypical necrobiosis lipoidica of the face and scalp is believed by some authors to represent a variant of annular elastolytic granuloma, rather than true NL.

Ulcerated NL requires special therapeutic considerations. As described above, tacrolimus ointment 0.1% may help in the healing of NL-associated ulcers. In addition, topical granulocyte-colony stimulating-factor, topical bovine collagen particles, protease-modulating dressings, and hyperbaric oxygen have each been reported to be successful in healing ulcers associated with NL. Successful reports of hyperbaric oxygen generally describe healing after a prolonged number of treatment sessions (100 or more). Surgical approaches, such as skin grafts, may also be used for severe, ulcerated lesions of NL and are sometimes paired with immunomodulatory therapy, such as etanercept and prednisone.

An unusual clinical scenario is the diabetic patient who receives pancreas transplant or simultaneous pancreas-kidney transplant. Considerable improvement of NL has been incidentally noted following transplant surgery. Improvements in microcirculation, restoration of metabolic control, or therapy with immunosuppressive medications have been cited as possible explanations for the frequent resolution of NL following pancreas transplantation.

What is the Evidence?

(Comprehensive continuing medical education (CME) review article from 1991 provides a thorough discussion of all aspects of NL, including a detailed discussion of theories of pathogenesis and treatment options available at that time.)

(This large series of 171 NL patients from Mayo Clinic found an association with diabetes mellitus in two-thirds of NL patients. The review includes a detailed description of clinical and histopathologic features. Intralesional corticosteroid injection is cited as a helpful therapy.)

(Case report of a 62-year-old woman with chronic ulcerated NL, unresponsive to prior therapies. Treatment with tacrolimus ointment 0.1% was associated with healing of the ulcer, even though the underlying plaque of NL persisted. This report suggests the usefulness of tacrolimus ointment, particularly when ulceration is present.)

(Seven patients received twice weekly topical PUVA treatments using a protocol similar to those for localized psoriasis. Two patients withdrew from the study early due to a poor initial response to treatment. The remaining five patients received 23 to 62 treatment sessions and experienced a mean reduction in plaque area of 50%. Two patients experienced complete resolution of lesions. One patient with severe ulcerated NL healed during the course of treatment.)

(In this case report, a 20-year-old diabetic woman received oral pentoxiphylline 400mg three times daily. Initial signs of healing were observed after 3 months of therapy, and near resolution of lesions occurred after 6 months.)

(Six patients received a course of oral methylprednisolone 1 mg/kg/day by mouth for 1 week, followed by 40 mg/day for 4 weeks, then tapered and discontinued after 2 more weeks. All experienced marked improvement of disease activity. The benefit was long-lasting. At 7 months, no recurrences were noted. All patients tolerated the treatment well, even those with diabetes mellitus.)

(Case report of a 29-year-old diabetic woman with NL. Lesions improved significantly with etanercept 50mg injected subcutaneously twice weekly for 3 months, and then 1 weekly for an additional 5 months. Due to insurance reasons, she was switched to adalimumab 40mg subcutaneous weekly injections, but symptoms worsened. Switching back to etanercept resulted in clinical improvement.)

(Case report of a type I diabetic woman with NL, unresponsive to topical corticosteroids. A pretibial plaque of NL was injected intradermally with etanercept 25 mg at 1-cm intervals, after topical anesthesia with 4% lidocaine cream. Intralesional injections of etanercept into the plaque were repeated weekly. Initial improvement was noted at 1 month, and the plaque resolved after 8 months of treatment.)

(This retrospective review examines NL patients who underwent transplant of the pancreas, pancreas and kidney, or just kidney. The results suggest that NL is more likely to resolve after pancreas transplant than after kidney transplant alone. Improved metabolic control is identified as a likely cause of the improvement in this study.)